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Cyanide anion was used to attempt to trap possible imine intermediates in the oxidative N-dealkylation of propranolol (1). Reaction of 3-(1-naphthoxy)-1-amino-2-propanol (desisopropylpropranolol, 2) with acetone provided this expected intermediate in an approximately 7:1 ratio of oxazolidine 6 to imine 5, as determined by 1H NMR. The mixture when treated with sodium cyanide gave the expected alpha-aminonitrile 7. Microsomal oxidation of propranolol in the presence of sodium cyanide gave two cyanide-containing adducts as shown by GC-MS (12a and 12b). Using specifically deuterated propranolols (8, 9, 10, and 11) as substrates showed both of these cyanide-containing adducts to have lost the N-isopropyl group. Compounds 12a and 12b were shown to be diastereomeric alpha-aminonitriles arising from the reaction of 2 with propionaldehyde, a contaminant from the ether used for extraction, and cyanide anion. Authentic 7, stable to derivatization and GC-MS conditions, rapidly decomposed under the conditions of the metabolic experiments.

Preparation of the cis-and trans-4-hydroxy-3-trimethyl-ammoniumtetrahydrofuran and 4-acetoxy-3-trimethylammonium-tetrahydrofuran halides and 3-trimethylammoniumtetrahydrofuran iodide is described. Weak muscarinic activity was noted for the unsubstituted 3-trimethylammoniumtetrahydrofuran salt, being about 1000-fold less potent than acetylcholine. The trans-hydroxy and trans-acetoxy compounds showed even less activity, and the cis-compounds were inactive.

Six ring-fluorinated phenytoin analogs were synthesized, and their anticonvulsant activity in the maximal electroshock seizure and subcutaneous pentylenetetrazol assays was determined. 5-(4-Fluoro- phenyl)-5-phenylhydantoin, 5-(3-fluorophenyl)-5-phenylhydantoin, and 5,5-bis(4-fluorophenyl)hydantoin were active in the maximal electroshock seizure assay. The compounds were much less potent than phenytoin but showed an extremely long duration of action.

Oxprenolol (1), like related beta-adrenergic antagonists, undergoes oxidative N-dealkylation to form the corresponding 3-aryloxypropane-1,2-diol (2), 3-aryloxylactic acid (3), and 2-aryloxyacetic acid (4) metabolites. Compounds 3 and 4 were synthesized by conversion of 2-allyloxyphenol (5) to the aryloxyacetaldehyde 6 and subsequent elaboration to the desired acids. Both acids (3 and 4) and glycol 2 were confirmed as metabolites formed from 1 in vivo in the rat and in vitro in the rat liver 9000 X g supernatant fraction. Incubation of a pseudoracemate of 1, made up of equal molar amounts of (2S)-1-d0 and (2R)-1-d2, showed that 2 and 3 arise principally from (2S)-1 by S/R ratios of approximately 5:1 and 2:1, respectively. On the other hand, acetic acid derivative 4 arises about equally from both enantiomers of 1.

1,1-Diethoxy-3-(1-naphthoxy)-2-propanol (V), the diethyl acetal of an important aldehyde intermediate in the metabolic N-deal-kylation of propranolol, was prepared from compound X, the product of the reaction of the lithium salt of methyl methylsulfinylmethyl sulfide with 2-(1-naphthoxy)-acetaldehyde. Compound X, as a mixture of three diastereomeric alpha-hydroxydithioacetal derivatives, when treated with ethyl orthoformate afforded the desired acetal V as well as two ring-closure products, the dihydronaphtho[1,2-b]pyrans VI and VII. Compounds VI and VII were characterized on the basis of mass spectral and 1H- and 13C-NMR data. The stereochemistry of these compounds was assigned on the basis of the 300-MHz 1H-NMR spectra of their acetate esters (XI and XII).

Preparation of 6-endo and 6-exo-acetoxy-2-methylisoquinuclidine methiodides are described. Muscarinic assay data are reported. Neither of the compounds showed activity when compared to acetylcholine and 3-acetoxyquinuclidine methiodide.

The syntheses of endo- and exo-2-trimethylammonium-exo-5,6-epoxy-7-oxabicyclo[2.2.1]heptane iodides are reported. Muscarinic assay results are reported and compared with endo-and exo-2-trimethylammoniumbicyclo[2.2.1]heptane iodides. Of the compounds tested, only exo-2-trimethylammoniumbicyclo-[2.2.1]heptane iodide demonstrated muscarinic activity, but it was only marginally active.

The preparation of 1-methyl-2,3-benzo-6-oxabicyclo[3.2.1]octane-4,7-dione and 1-methyl-2,3-benzo-6-oxabicyclo[3.3.1]nonane-4,7-dione is reported by facile intramolecular cyclization of the corresponding bromotetralone. 4-Methyl-4-carboxyl-1-tetralone is cyclized under the conditions of bromination. 4-Methyl-1-tetralone-4-acetic acid is cyclized only on continued heating of the α-bromoketone in acetic acid.

Amphetamine analogs 10(e)- and 10(a)-amino-1,2,3,4,4a,9,10,10a-(trans-4a,10a)-octahydrophenanthrene, I and II, respectively, were prepared. Hydrogenolysis (methanolic hydrochloric acid) of 9(a)-hydroxy-10(e)-amino-1,2,3,4,4a,9,10,10a-(trans-4a,10a)-octahydrophenanthrene afforded I. A similar procedure for the preparation of II from 9(a)-hydroxy-10(a)-amino-1,2,3,4,4a,9,10,10a-(trans,-4a,10a)-octahydrophenanthrene was followed, except the more drastic conditions of a mixture of acetic and perchloric acids were necessary. The compounds were inactive when assayed for amphetamine behavioral and hyperthermia effects.